The present invention relates to an improved method particularly for producing dimer alkaloid compounds especially of the Vinca alkaloid group and in particularly is an improved method for producing the antiviral, antileukemic compounds vincristine and vinblastine of Formula A. ##STR1## The above compound, when R is COOCH.sub.3, and R.sub.1 is OCH.sub.3, is vinblastine (NSC 49482) and when R is COOCH.sub.3, R.sub.1 is OCH.sub.3 and N.sub.1 is N-CHO (N-formyl), vincristine (NSC 67574).
Novel 3',4'-dehydro compounds of Formula B can also be made in accordance with the method of this invention. ##STR2##
3',4'-Dehydrovinblastine N-methylamide (NSC 256954) is a compound of Formula B wherein R is COOCH.sub.3 and R.sub.1 is NHCH.sub.3. 18'-Decarbomethoxy-3',4'-dehydrovinblastine N-methylamide (NSC 258372) is a compound of Formula B wherein R is H and R.sub.1 is NHCH.sub.3. Corresponding vincristine compounds are those wherein the group at N, of the vindoline unit, is N-CHO (N-formyl).
This invention further relates to novel anti-leukemic 3',4'-dehydrovinblastine and vincristine compounds of Formula B as well as 4'-deoxo compounds, which otherwise correspond to those of Formula B, but in which the 3',4'-bond is saturated.
Representative members of the novel series of compounds showed anti-leukemic activity, particularly against L1210 and P388 mouse leukemia, the novel compounds being those of the formula ##STR3## wherein Q is a single or double bond at the 3',4'-position of an indole unit, which, with a dihydroindole unit, constitutes a dimeric vincristine or vinblastine compound; P is a single or double bond; R is H or COO-alk and alk is alkyl of 1-6 carbon atoms; R.sub.1 is O-alk, NH.sub.2, NH-alk, N(alk).sub.2 or NHNH.sub.2 and alkyl is of 1-6 carbon atoms; and R.sub.2 is methyl or formyl.
Novel compounds of the invention include those of the above formula, more particularly those wherein:
(a) Q is a single bond; PA1 (b) Q is a double bond; PA1 (c) R is H, including each of (a)-(b); PA1 (d) R is COO-alk, including each of (a)-(b); PA1 (e) R.sub.1 is O-alk, including each of (a)-(d); PA1 (f) R.sub.1 is NH.sub.2 or NH-alk, including each of (a)-(d); PA1 (g) R.sub.2 is CH.sub.3, including each of (a)-(f); PA1 (h) R.sub.2 is CHO, including each of (a)-(f); PA1 (i) P is a single bond, including each of (a)-(h); PA1 (j) P is a double bond, including each of (a)-(h).
and
Of the novel compounds of the invention, those which are particularly preferred are:
(A) 4'-deoxovinblastine compounds, especially 4'-deoxovinblastine (NSC 250834), obtained from coupling dihydrocatharanthine and vindoline; or 4'-deoxodihydrovinblastine (NSC 256952), obtained from coupling dihydrocatharanthine and dihydrovindoline;
(B) 3',4'-dehydrovinblastine compounds, especially 3',4'-dehydrovinblastine (NSC 250833), from coupling catharanthine and vindoline; 3',4'-dehydro-18'-decarbomethoxyvinblastine, from decarbomethoxycatharanthine and vindoline; 3',4'-dehydrovinblastine amide, from catharanthine and vindoline amide; 3',4'-dehydrovinblastine N-methylamide (NSC 256954), from catharanthine and vindoline N-methylamide; 3',4'-dehydro-18'-decarbomethoxyvinblastine N-methylamide (NSC 258372), from decarbomethoxycatharanthine and vindoline N-methylamide; or 3',4'-dehydro-6,7-dihydrovinblastine (NSC 256953), from catharanthine and dihydrovindoline;
(c) 4'-deoxovincristine, from coupling of dihydrocatharanthine and N-formylvindoline; and
(d) 3',4'-dehydrovincristine compounds, especially 3',4'-dehydrovincristine, from the coupling of catharanthine and N-formylvindoline; 3',4'-dehydro-18'-decarbomethoxyvincristine, from decarbomethoxycatharanthine and N-formylvindoline; 3',4'-dehydrovincristine amide, from catharanthine and N-formylvindoline amide; 3',4'-dehydrovincristine N-methylamide, from catharanthine and N-formylvindoline N-methylamide; or 3',4'-dehydro-18'-decarbomethoxyvincristine N-methylamide from decarbomethoxycatharanthine and N-formylvindoline N-methylamide.
The present series of dimeric alkaloids, including important antitumor agents, are formed from an indole, such as catharanthine, and a dihydroindole unit, e.g., vindoline, in which the halves are linked via a carbon-carbon bond involving an aliphatic center C.sub.18 in the indole unit and an aromatic carbon C.sub.15 in the vindoline portion. Specifically, where the catharanthine unit possesses a hydroxyl group at C.sub.4, the dimer produced with vindoline will be vinblastine and also the similar catharanthine unit linked to formyl vindoline will produce vincristine.
It is further noted in the formula above that additive or substituent compounds such as amides and alkoxy compounds at C.sub.3 and C.sub.4 have been prepared from plant recovered vinblastine and vincristine.
In a broad sense the present method is applicable to the production of dimer products from catharanthine and dihydrocatharanthine with vindoline as starting materials and phenyl, alkyl and amide derivatives embraced by the following formulas: ##STR4##
Formula I is as pictured and in that formula alk represents a lower alkyl group of C.sub.1 -C.sub.6 and preferably C.sub.1 -C.sub.3 ; aryl is mono-aryl such as benzyl, styryl, and xylyl; R.sub.1 is a member of the group consisting of hydrogen, alk, CHO and COR.sub.5 where R.sub.5 is alkyl or aryl; R.sub.2 and R.sub.3 are members of the group consisting of hydrogen and --CO--alk: R.sub.4 is a member of the group consisting of COO--alk, CONH--NH.sub.2, CONH.sub.2, CONHR.sub.6, and CON(R.sub.6).sub.2 where R.sub. is alkyl; Z is a member of the group consisting of --CH.sub.2 --CH.sub.2 -- and --CH.dbd.CH-- and R is a member of the indole family represented by
Formula II where R.sub.7 is a member of the group consisting of hydrogen, or COO--alk: R.sub.8 is a member of the group consisting of hydrogen, OH, O--alk, OCO--alk or alkyl; R.sub.9 is a member of the group consisting of hydrogen, OH, O--alk, OCO--alk, or alk; R.sub.10 is a member of the group consisting of hydrogen, OH, O--alk, OCO--alk, or
Formula III where R.sub.11 is a member of the group consisting of hydrogen or COO--alk: R.sub.12 is a member consisting of alkyl.
Compounds represented by Formula I are prepared by contacting vindoline or a vindoline derivative, when R is hydrogen, with an indole derivative represented by a compound of
Formula IV where R.sub.13 is a member of the group consisting of hydrogen or COO--alk COO--alk by a compound of
Formula V where R.sub.14 is a member of the group consisting of hydrogen or COO-alk and R.sub.15 is a member of the group consisting of alkyl.
In Formulas I-VI and generally in this application and claims, alk and alkyl mean lower alkyl as defined in Formula I above and aryl means mono-aryl as similarly defined in Formula I. ##STR5##
The so-called intermediates IV and V are not isolated during the process of the present invention and this factor is believed significantly and favorably influence the stereochemistry to produce the natural isomers at C.sub.18'. The conditions for the complete reaction including the formation of the NO compound IV and V as well as the formation of the indoledihydroindole dimers represented by Formula I are carried out in an inert organic solvent such as preferably methylene chloride containing trifluoroacetic anhydride. As alternatives for methylene chloride useful in producing the NO compound, there may be used other polyhalo organic solvents such as carbon tetrachloride, methylene bromide, and chloroform.
As alternative reagents for the trifluoroacetic anhydride component used in fragmentation and coupling, there may be utilized trichloroacetic anhydride, acetic anhydride, acetyl chloride, and tosyl anhydride. These reagents bring about a Polonovski-type fragmentation of the C.sub.5 -C.sub.18 bond in the substances shown in Formulas IV and V.
The reaction temperature, time, and pressure conditions in general are similar to those employed in the Polonovski reaction which, in its original application, involved the dealkylation of tertiary and heterocyclic amines by acylation of the corresponding N-oxides with acetic anhydride or acetyl chloride (cf. Merck Index, 8th ed., 1968, page 1203). The temperature of the fragmentation reaction may vary from -15.degree. C. to 40.degree. C. and preferably from -10.degree. C. to +10.degree. C. The portions of the reaction relating to the formation of the NO compound are conducted in the open but the coupling following the fragmentation portion of the reaction is conducted under cover with inert conditions such as nitrogen or an inert gas of Group Zero of the Periodic Table such as argon, neon, helium, etc., and under a positive temperature control of about 10.degree. C. to -10.degree. C. In the present combined reaction where fragmentation and coupling occur sequentially, the temperature control preferred of 10.degree. to -10.degree. C. and optimally -10.degree. C. for both fragmentation and coupling, together with an inert blanket is greatly preferred.
Due to the low temperature necessary for the latter stage reaction, the reaction time may vary from several hours for several days.